TYPE Review
PUBLISHED  10 July 2023
OPEN ACCESS
EDITED BY
Deep Jyoti Bhuyan,
Western Sydney University, Australia
REVIEWED BY
Mahsa Jalili,
University of Copenhagen, Denmark
Naser Alsharairi,
Griffith University, Australia
*CORRESPONDENCE
Maria Rosaria Corbo
mariarosaria.corbo@unifg.it
These authors have contributed equally to this
† balanced composition (referred as eubiosis) is necessary for several physiological
work
RECEIVED 21April 2023
ACCEPTED 26 June 2023
PUBLISHED 10 July 2023
CITATION
Campaniello D, Bevilacqua A, Speranza B,
Racioppo A, Sinigaglia M and Corbo MR (2023)
A narrative review on the use of probiotics in
several diseases. Evidence and perspectives.
Front. Nutr. 10:1209238.
doi: 10.3389/fnut.2023.1209238
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© 2023 Campaniello, Bevilacqua, Speranza,
Racioppo, Sinigaglia and Corbo. This is an
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Frontiers in Nutrition
DOI 10.3389/fnut.2023.1209238
A narrative review on the use of
probiotics in several diseases.
Evidence and perspectives
Daniela Campaniello †, Antonio Bevilacqua †, Barbara Speranza ,
Angela Racioppo , Milena Sinigaglia  and Maria Rosaria Corbo *
Department of Agriculture, Food, Natural Resources and Engineering, University of Foggia, Foggia, Italy
Gut microbiota is a complex ecosystem, strictly linked to health and disease, as a
functions, while an unbalanced composition (dysbiosis) is often associated to
pathological conditions and/or diseases. An altered microbiota could be positively
affected and partially restored through probiotic supplementation, among others.
This review addresses the effects of probiotics in several conditions, used as case-
studies (colorectal cancer, neuro-psychiatric diseases, intestinal diseases, obesity,
diabetes, metabolic syndrome, immune system, and musculoskeletal system
disorders) by pointing out the clinical outcomes, the mode of action, mainly
related to the production of short chain fatty acids (SCFA), the impact of probiotic
dose and mode of supplementation, as well as trying to highlight a hit of the most
used genera.
KEYWORDS
probiotics, disease, clinical trials, effects, genera
1. Introduction
Since 2001, Lederbergh and McCray highlighted the importance of microorganisms
inhabiting the human body in health and disease; in fact, a close connection between the “state
of health” of microbial communities and human health was recognized as a milestone (1, 2).
Nowadays, “the assemblage of microorganisms (bacteria, archaea, eukaryotes, and viruses)
present in a defined environment” is called Microbiota (3) and its composition changes
according to the surrounding environment. In particular, the microbiota of the gastro-intestinal
tract, generally known as gut microbiota, is a complex ecosystem composed of fungi, viruses,
and bacteria, adapted to live on the mucus surface of the intestine or in its lumen, affected,
among others, by the modality of childbirth (vaginal vs. cesarean), initial nutrition (breastfeeding
vs. formula) and by the guest genotype (4).
The microbial ecosystem balance is called eubiosis and this status allows to perform several
functions (nutritional, immunological, preventive actions, etc.); but, if this balance is lacking or
altered, there is a condition of “dysbiosis.” Dysbiosis status is often associated to various diseases,
such as asthma, chronic intestinal diseases, obesity, diabetes mellitus, psychiatric disorders, and
many others (5). Several factors, such as antibiotics, smoking, alcohol, a sedentary life, diets low
in fiber, poor chewing, psychophysical stress, chemotherapy, or abuse of drugs (laxatives,
antidepressants, sleeping pills, analgesics) heavily affect microbiota balance and could lead to a
dysbiotic status (6). An altered microbiota could be positively affected and partially restored
through correct diet, and physical activity, although sometimes a supplementation of probiotics
and/or prebiotics (e.g., fibers) could be necessary (7).
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According to the definition of Food and Agriculture Organization/
World Health Organization (8), slightly modified by Hill et al. (9),
probiotics are “Live microorganisms which when administered in
adequate amounts confer a health benefit on the host.” They represent
a strategy to treat intestinal dysbiosis, as they could exert some
important functions, that is (i) anti-inflammatory activity, essential for
maintaining the immune response; (ii) to prevent the colonization by
pathogenic microorganisms thanks to the physical barrier function;
(iii) to produce antimicrobial substances (10). Thousands of authors
studied probiotics and their effects on a wide variety of conditions; a
search done on Scopus using two keywords (probiotics and disease)
revealed for 2022–2023 more than 4,000 papers (research papers or
reviews). The analysis of keywords and abstracts through VosViewer,
a tool for networking and clustering of citations and reference details,
pointed out a cluster linked to the effects of probiotics on many
diseases (red clusters in Figure 1), including among others diabetes,
liver diseases, cancer, neurological diseases, obesity etc., thus
suggesting the interest toward this topic, also stressed by an overview
on clinicaltrials.gov. When the search on this database was done (April
2023), there were more than 2000 items, addressing more than 900
conditions, mainly in Europe and United States (Figure 2).
The papers available on PubMed, and Scopus have some common
keywords (intestinal flora, gut microbiota, microbiome) and generally
postulate that the beneficial effect of probiotics relies upon the
modulation of gut microbiota. In addition, another mode of action of
probiotic into the gut is connected to the improvement of gut barrier
mucosa; in fact, both an eubiotic gut microbiota and probiotics act at
FIGURE 1
Clustering and most frequent keywords for the research papers and reviews published in 2022 and 2023 on the effects of probiotics on several disease.
Elaboration through the software VosViewer.
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10.3389/fnut.2023.1209238
the level of signaling pathways, thus they cause an increase of the
mucus, an enhanced production of defensins and proteins in the tight
junctions (11). Finally, probiotics, could act on the immune systems,
through its direct modulation or indirectly acting on gut microbiota.
It has been reported that 70% of immune cells are in the intestine,
mainly in the small bowel, where they constitute the gut associated
lymphoid tissue (GALT) (11), thus suggesting that gut is the main site
of interaction between host immune systems and commensal
microorganisms, either positive or pathogenic. Generally, the
activation of the immune system is first based on the recognition of
PRRs (pattern recognition receptors) by the microbial associated
molecular patterns (MAMPs); MAMPs are components of microbial
surface able to interact with the gut epithelium and stimulate the cells
of the gut immune system at the lamina propria level (11). Therefore,
T lymphocytes are activated, and helper T lymphocytes (Th) are
differentiated, by favoring pro- or anti-inflammatory cytokines
production (11).
Generally, an eubiotic gut microbiota and probiotics positively
affect both host’s innate and adaptive immunity (12); concerning
innate immunity, gut microbiota acts both locally and systemically, by
influencing the development and function of antigen presenting cells
(APCs), neutrophils and other innate cell types (12). Moreover, it has
been reported the ability of gut microbiota and of some probiotics to
affect innate immunity outside the gut milieu, for example by
promoting the attenuation of inflammation processes at local levels
(13, 14). There is also a role on adaptive immunity, due to the effect in
the development of the most important subtypes of CD4+ T cells (or
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FIGURE 2
Studies on probiotics on clinicaltrials.gov.
helper T cells, which are lymphocytes coordinating the response to
diseases), that is Th1, Th2, Th17 and Treg (12, 15). In addition to T cells,
an eubiotic gut microbiota could influence B cell maturation and
immunoglobulin production (16).
The mechanisms by which gut microbiota and probiotics
influence immune system include the production of various
compounds; SCFA (short chain fatty acids; butyrate, acetate, formate),
indole derivatives, and bile salts are, among others, the most
important. An extensive description of the effects of indole derivatives
on gut microbiota is in the review of Ye et al. (17); however, it is worth
mentioning that indole derivatives, produced by gut microbes and
some probiotic strains (e.g., Limosilactobacillus reuteri) through the
metabolism of tryptophan are crucial, because they enhance intestinal
epithelial cell function by regulating several genes involved in
mechanical barrier formation. Moreover, they increase mucin and
goblet cell secretion products, responsible of barrier of gut mucosa,
and reduce the impact of possible pathogens (17).
SCFA are produced through the fermentation of non-digestible
carbohydrates and amino acids in the colon and play a major role in
maintaining the barrier function of gut (18). They are absorbed by the
colonocytes and used as fuel for the colonic mucosal epithelial cells
(19), but at the same time they directly act on gut mucosa; for example,
butyrate contributes to reduce oxidative stress, thus stabilizing gut
mucosa and reducing the translocation of LPS (Lipopolysaccharide)
(12). Also, bile salts are essential for immunity in a bidirectional
crosstalk between host and microbiota. Primary bile salts, or host-
derived bile salts, shape and modify the composition of microbiota,
generally reducing the levels of Gram-negative bacteria; while those
synthesized by microbiota contribute to a further modulation of
microbiota itself and act on both innate and adaptive immunity, for
example by reducing the levels of pro-inflammatory cytokines, or
enhancing Treg cells differentiation (20).
SCFA and derivatives from tryptophan could also play a
significant role in reducing inflammatory status. SCFA bind to specific
receptors on intestinal epithelial cells, thus they inhibit NF-κB
pathway, Treg cell suppression, and pro-inflammatory cytokine
production by neutrophils and macrophages (21). For example,
butyrate could control gut inflammation through the induction of Treg
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10.3389/fnut.2023.1209238
cell differentiation (22). In addition, tryptophan (deriving from diet)
and indolic acid derivatives (for example IPA, indole-3-propionic
acid) bind to receptors expressed on immune cells, promote IL-10
production with anti-inflammatory activity and decrease TNF-α
release (21).
It is worth mentioning that the ability of potential probiotics to
modulate the immune system and ameliorate inflammatory status
depend on the strains and a comprehensive overview of the effects at
species level is missing (23). Other topics missing in the literature are
the technological aspects of the problems (production and dose of
probiotics). Therefore, the main goal of this paper is an overview of
the effects of probiotics on some representative conditions, addressing
some key-points, like the clinical effects, and the mode of action of
probiotics, if available; the elucidation of aspects common to all strains
of a species, and finally a focus on the importance of a correct dose.
There are many pathological conditions; however, by authors’
choice only research papers and some representative conditions were
chosen, as best models for future studies, that is colorectal cancer,
neuro-psychiatric diseases, intestinal diseases, obesity, diabetes,
metabolic syndrome, which are probably the most addressed topics in
the literature, along with two minor issues (immune system, and
musculoskeletal system disorders), which are promising ways but with
a few evidence.
For each pathological conditions, the effects of probiotics are
described, and the list of studies and outcomes is in reported, along
with the kind of probiotic, or the probiotics mix, the target of the study
(humans or animal model), and the achievable and measurable
outcomes (Supplementary Table S1).
2. Colorectal cancer
Colorectal cancer (CRC) is the most frequent neoplastic form of
the gastrointestinal tract; its incidence is experiencing a progressive
increase, due to a gradual aging of the population, the adoption of
sedentary lifestyle, and unbalanced diets (24), as also suggested by the
higher incidence rates in Australia and New Zealand, North America,
and Europe (25). Although it is a multi-etiological condition, it should
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be considered the genetic susceptibility of each individual, as well as
some environmental factors connected to carcinogenesis, like caloric
intake, obesity, alcohol or smoking (26–37). Focusing on gut
microbiota, CRC patients often develop a dysbiosis due to the use of
antibiotics, radiation therapy, and chemotherapy, and their gut
microbiota is characterized by an increased pathogenic bacteria
abundance, decreased SCFA-producing bacteria and SCFA levels (38,
39) and butyrate seems the most affected compound, as it could
be successfully used as a potential biomarker of CRC risk or as an early
warning signal of the disease onset (40). Conversely, high levels of
SCFA have antineoplastic properties, due to a combination of several
mechanisms, like the downregulation of the canonical Wnt signaling
pathway linked to colonic carcinogenesis, the limitation of
proliferation and migration of neoplastic cells, the suppression of
tumor angiogenesis, the induction of apoptosis and the promotion of
neoplastic colonocytes differentiation (40).
Although the production of SCFA probably exerts a major role in the
anti-carcinogenic activity of probiotics, there are also some other direct
and indirect effects, briefly summarized in Figure 3, including the ability
to catch and adsorb carcinogenic compounds, as well as by stimulating
host’s antitumor activity through the stabilization of the tight junctions
or the production of defensins. Other effects include the antagonistic
activity toward putrefactive microbiota and the creation of a
microenvironment into the colon unfavorable for the carcinogenesis.
Many research papers and clinical trials have addressed the role
of probiotics in the CRC onset and/or mitigation and a comprehensive
overview of the most important trials is in the paper of Hou et al. (40);
Supplementary Table S1 shows some relevant studies. In particular,
Bacteroides fragilis exerts anti-inflammatory and anticancer effect, as
it can alter the composition of the microbiota, inactivating
carcinogenic compounds, competing with pathogens or
CRC-promoting bacteria and stimulating the immune response (41);
FIGURE 3
Probiotic effects on CRC.
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10.3389/fnut.2023.1209238
similar effects could be observed for Lactobacillus acidophilus MTCC
5401 (42) and Faecalibacterium prausnitzii (43), while Lactococcus
lactis subsp. cremoris C60 and Lacticaseibacillus casei ATCC334
probably exerted a preventive and an inhibitory effect on the cells
responsible for CRC (44, 45). In addition, an emergent butyrate-
producing probiotic, Butyricicoccus pullicaecorum exerted antitumor
effect and showed good acid and bile tolerance; it was also able to
reduce pathogen population and to prevent necrotic enteritis (41).
Shang et al. (46) demonstrated the effectiveness of a probiotic mix
composed of Bifidobacterium longum, Bifidobacterium bifidum,
L. acidophilus and Lactiplantibacillus plantarum in mice, able to
reduce the tendency of CRC cells to migrate in different body tissues.
Furthermore, the tumor size in mice feed with probiotic mixture was
significantly smaller than the control group. In another study, Dong
et al. (47) investigated Ligilactobacillus salivarius effect on CRC cells,
via oral administration in male mice. The authors reported that
probiotic induced the suppression of dimethylhydrazine (DMH)
production, both in the early and post-early stages of carcinogenesis.
DMH is a potent carcinogen used to induce colon cancers in animals,
particularly mice. These results therefore suggest that daily oral
administration of L. salivarius could effectively prevent CRC
carcinogenesis by inhibiting cell proliferation and inducing apoptosis
in DMH-induced tumor models.
Probiotics could also counteract dysbiosis occurring in most
patients after CRC resection and improve the biodiversity of bacterial
biota. In this context, Park et  al. (48) observed improvements in
postoperative intestinal dysbiosis with the use of probiotics in CRC
surgical resection patients. Sixty patients, aged between 18 and 75,
with sigmoid colon adenocarcinoma and anterior resection of the
same, were divided into two groups: 29 and 31 patients feed with a
probiotic mixture (Bifidobacterium animalis subsp. lactis HY8002,
L. casei HY2782 and L. plantarum HY7712) and the placebo
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respectively, for 4 weeks. Probiotics led to an increased production of
SCFA by colon bacteria, decreased microbes associated with the
development of CRC (mainly Alloprevotella and Porphyromonas) and
improved postoperative recovery of patients. Particularly interesting
were the data obtained from the measurement of faecal zonulin, a
protein that acts on the tight junctions of the intestine, regulating its
permeability; high levels are associated with a deterioration of the
intestinal mucosa, which does not adequately perform its protective
function. The authors found that zonulin significantly decreased in the
group fed with probiotic mixture compared to the placebo group.
The efficiency of L. plantarum was also observed by Yoon et al.
(49); the authors evaluated the effect of L. plantarum CJLP243
(isolated from kimchi, a traditional fermented product of Korea) on
intestinal function and quality of life toward 36 patients aged 20–75,
who have undergone rectal resection and were admitted undergoing
the reversal of the ileostomy. Unfortunately, a significant number of
patients reported symptoms including diarrhea, fecal incontinence,
and other complications. The patients were divided into two groups:
19 and 17 patients who took placebo and probiotic respectively, once
a day for the duration of 3 weeks. The results showed that there were
no significant differences between the two groups regarding the
improvement of symptoms; however, by comparing the post-operative
results between the first and third weeks, the administration of the
probiotic showed a tendency to improve intestinal function and
quality of life.
3. Neuro-psychiatric diseases
Many human and animal studies support the idea that gut
microbiota plays an important role for cognitive functions, in the
regulation of mood and emotions, and in the interpersonal
interactions and communications (50). Gut microbiota can modulate
brain activity and behavior; therefore, its manipulation can be applied
in the treatment of neuropsychiatric disorders such as autism
spectrum disorders, depression, etc. (51, 52). The idea that probiotic
could positively affect the clinical outcomes of depression was first
postulated in 1910 when Hubert J. Norman and Georges Porter
Philipps found an improvement in the symptoms after taking
lactobacilli (53). Later then, this idea has been confirmed by several
studies and clinical trials, although the mode of action of probiotic on
behavior and neuro-psychiatric diseases is still unclear, as in some
cases symptoms improvement and amelioration are not related to a
modification in gut microbiota (53).
Supplementary Table S1 reports 33 scientific articles concerning
the effect of probiotics in subjects with neuro-psychiatric diseases.
Twelve articles refer to autism (ASD), a neurobiological developmental
disorder, characterized by severe and generalized impairment of both
communication skills and social interaction. Subjects affected by ASD,
especially in children aged 2 to 11 years, show a stereotypical use of
movements, language or objects, excessive adherence to routine
situations, routines, rituals, and fixation for particular or restricted
interests abnormally in duration or intensity (54). The benefits of
probiotics depend on the microorganisms. For example, an anti-
inflammatory effect was found following the administration of
Bifidobacterium spp. (55), while improvement of gastrointestinal
disorders and neuro-behavioral symptoms was achieved by microbial
mixtures composed of several strains of Bifidobacterium, Lactobacillus,
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Streptococcus genera as well as L. plantarum PS128, Limosilactobacillus
reuteri and Lacticaseibacillus rhamnosus GG (56–62). In particular, the
effectiveness of L. plantarum PS128 relied upon the age of the children,
as the best results were obtained on infants (60).
For anxiety and depression, the outputs showed an improvement
in the gut microbiota with a reduction in depressive and anxious
behavior (63–65). In particular, Abildgaard et  al. (64) proposed a
mixture of probiotics (B. bifidum W23, Bifidobacterium lactis W52,
L. acidophilus W37, Levilactobacillus brevis W63, L. casei W56,
L. salivarius W24, Lactococcus lactis W19, L. lactis W58) as potential
treatment strategy in major depressive disorders (MDD) to reduce
depressive behavior. Some studies reported improvement in behavioral
abnormalities and reduction in the main symptoms of depression in
humans, after the administration of strains belonging to the genera
Lactobacillus and Bifidobacterium (66–71). Another possible use of
probiotics refers to dementia and cognitive deterioration. The intake
of Enterococcus faecium together with inulin (72) and Bifidobacterium
breve A1 (73) improved learning and memory skills, language,
attention and orientation in the elderly people. In addition, some
studies on animals showed an improvement in the intestinal barrier
and spatial learning through the administration of L. casei LC122, of
B. longum BL986 and of Clostridium butyricum (74, 75).
For Parkinson’s disease (PD) Tamtajii et al. (76) and Magistrelli
et  al. (77) observed that L. acidophilus, B. bifidum, L. reuteri,
Limosilactobacillus fermentum and L. salivarius allowed an
improvement in MDS-UPDRS (Movement Disorder Society-Unified
Parkinson’s Disease Rating Scale) scores and a significant reduction in
pro-inflammatory cytokine levels and reactive oxygen species (ROS),
with a possible weight of the stage of the disease and sex. In animal
models, Barichella et al. (78) showed that the genera Lactobacillus and
Bifidobacterium could improve intestinal integrity and reduce anxiety,
depression and stress.
Anorexia nervosa (AN) consists of an altered perception of one’s
own body, in particular weight. In fact, people who are in this
condition try to keep their body weight as low as possible through a
strong dietary restriction, inducing vomiting and practicing intense
physical activity. AN most frequently affects young women, although
recently it has also targeted men; it can often be  associated with
psychological problems such as depression, anxiety, low self-esteem,
alcohol abuse, and self-harm (79, 80). L. plantarum P8 determined a
reduction in anxiety and stress (81) while B. fragilis reduced gastro-
intestinal pains and caused as a secondary effect an increase serotonin
production (82); it is not clear if these effects have a connection or are
independent outcomes (Supplementary Table S1). In animals,
Lactobacillus spp. promoted weight gain (83) and improved the
behavioral abnormalities in stressed mice involving the microbiota-
brain gut axis (84). Moreover, Akkermansia muciniphila, considered a
potential candidate for improving metabolic disorders associated with
anorexia, obesity, diabetes, liver disease, favored the restoration of a
compromised intestinal barrier (85).
Probiotics were also studied in relation to the benefits they bring for
other diseases affecting the brain systems. For example, the
administration of L. acidophilus, B. bifidum and B. longum, improved the
cognitive function of Alzheimer’s patients (humans and in animals) (86,
87), while strains of L. rhamnosus GG and B. animalis subsp. lactis Bb12
led to an improvement of the symptoms related to schizophrenia (such
as delirium, hallucinations, language, and disorganized behavior, etc.)
(88). Furthermore, in women aged 20–40 affected by multiple sclerosis,
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a mixture of probiotics (Lacticaseibacillus paracasei, L. plantarum,
L. acidophilus, L. delbrueckii, B. longum, Bifidobacterium infantis,
B. breve, Streptococcus thermophilus) improved the symptoms by
modulating the anti-inflammatory immune response (89). Referring to
multiple sclerosis, Altieri et al. (90) in a recent review described how
microbiota change in MS patients and proposed probiotics as useful
tools to improve the symptoms of MS patients.
4. Intestinal diseases
Generally, probiotics could positively impact on gastrointestinal
disorders (GI) (abdominal pain or discomfort, swelling and flatulence)
through metabolic effects resulting from enzymatic activity and the
crosstalk with the central nervous system, by improving gut function
(91). In addition, there are several evidence on positive effects on
Inflammatory Bowel Disease (IBD) and Irritable Bowel
Syndrome (IBS).
Concerning IBD, Ferreira-Halder et al. (43) and Lopetuso et al.
(92) highlighted the anti-inflammatory effect performed by
F. prausnitzii and A. muciniphila. F. prausnitzii contributes
substantially to the health of the intestine and is considered a
biomarker not only for human health but also for diagnosis and
subsequent treatment (43). On the other hand, A. muciniphila has
been shown to be effective in immune and metabolic regulation; it
ensures increased function of the intestinal barrier showing a direct
and beneficial effect on the host’s response. In addition, its use is
considered safe if aimed at human studies (93).
In patients with ulcerative colitis, probiotics act as a barrier against
harmful microorganisms. A consortium of 8 probiotic strains (VSL3,
composed of L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp.
bulgaricus, B. longum subsp. longum, B. breve and B. longum subsp.
infantis, Streptococcus salivarius subsp. thermophilus) was effective in
maintaining a state of remission (94), while Azad et al. (95) reported
that Lb. acidophilus restored the balance of inflammatory cytokines
and Th17/Treg cells in mice induced colitis, and showed beneficial
effects in the prevention of cancer and intestinal inflammation (95).
In addition, several analyses have shown the effectiveness of the
administration of probiotics in premature infants, with a reduction of
both the development of enterocolitis and the risk of sepsis in old age.
In particular, Dermyshi et  al. (96) supported the benefits of
L. acidophilus-B. infantis blend.
IBS causes swelling, vomiting, diarrhea, abdominal pain,
frequency of stools, and probiotics could improve these symptoms.
Two formulations containing different probiotic strains
(F1 = L. acidophilus, L. reuteri; F2 = L. plantarum, L. rhamnosus,
B. animalis subsp. lactis) were administered to humans, thus gaining
a relief in bloating, abdominal pain, constipation, abdominal cramps,
and flatulence (97). Similar effects were observed through the
administration of Bacillus coagulans MTCC 5856 (98), and
L. plantarum DSM 9843 (99). Other studies reported the improvement
of IBS symptoms due to several lactobacilli (100, 101).
5. Obesity
Gut microbiota is involved in the control of body weight, energy
homeostasis and inflammation states; therefore, it plays an important
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10.3389/fnut.2023.1209238
role in the pathophysiology of obesity. Firmicutes and Bacteroidetes
are the two phyla involved in microbial dysbiosis and in the
development of obesity. The ratio between these phyla is very
important; in fact, Bervoets et al. (102) studied the gut microbiota of
26 overweight and obese children and 27 skinny children and found
that obese children have a higher ratio of Firmicutes to Bacteroidetes.
Supplementary Table S1 focuses on some application of probiotics
toward overweight and obese subjects. Kadooka et  al. (103)
administered fermented milk containing Lactobacillus gasseri
SBT2055 (200 g/day) to 87 overweight adults for 12 weeks. Reductions
in visceral and subcutaneous fat, body weight and BMI (Body Mass
Index) compared to the control group, were observed. Furthermore,
the consumption of yogurts supplemented with capsules, containing
109 CFU of Lactobacillus amylovorus and L. fermentum by 28
overweight participants, led to a reduction in total body fat mass
(104). Regarding gut microbiota, the researchers observed a significant
reduction of Clostridium cluster IV (for L. amylovorus consumption),
together with an increase of Lactobacillus in both treatments and
concluded that when the gut microbial composition is modulated
through probiotic consumption, this can positively alter energy
metabolism and body composition (104). An additional study on 70
overweight and obese children revealed that a combination of
probiotics, prebiotics and vitamins A, E and C for 8 weeks, significantly
reduced BMI, waist circumference, waist/hip ratio, LDL cholesterol
and triglycerides (105).
Probiotics can reduce cholesterol levels through bile salt hydrolase
(an enzyme that hydrolyzes bile salts into amino acid residues and free
bile salts). 200 g/day of yogurt containing S. thermophilus, L. delbrueckii
subsp. bulgaricus, L. acidophilus LA-5, and B. animalis BB12 for
9 weeks to 70 women in the third trimester of pregnancy resulted in
significant reductions in total cholesterol, LDL cholesterol, and high-
density lipoprotein (HDL) cholesterol, as well as serum triglyceride
concentrations (106). Probiotic supplementation also reduced blood
lipid concentrations (107).
A. muciniphila administered to animals led to a reduction in fat
mass and body weight; moreover, it favored the restoration of the
intestinal barrier function and, if administered to humans,
improved inflammation, insulin resistance and blood sugar
level (108).
Many authors reported that the action of probiotic toward obesity
is mediated by SCFA, which probably could be  involved in body
weight regulation, and maintenance, as well as in energy intake and
expenditure (109–111). Although there are several hypotheses, the
most probable mechanism involves the ability of propionate and
butyrate to bind to G-protein-coupled receptors in the colon leading
to the production of the gut hormones peptide YY and glucagon-like
peptide 1, thus influencing satiety and glucose homeostasis (109). In
addition, SCFA activate intestinal gluconeogenesis, and the released
glucose mediates a signal to brain through portal nerves for satiety
and insulin sensitivity, or they can also affect peripheral metabolism
in the liver (enhanced lipid oxidation, lower lipid storage), skeletal
muscles (increase of glycogen synthesis and reduction of glycolysis),
pancreas (increase of insulin and reduction of glucagon synthesis and
release) or adipose tissue (reduction of insulin mediated adiposity)
(109, 110). The evidence available in the literature suggest that that
increasing SCFA production could be  a preventive measure to
counteract gastro-intestinal dysfunction, obesity, and type 2 diabetes
mellitus (109, 110), although longer term trials and data are required,
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also to elucidate the exact role of the initial imprinting of gut
microbiota and how it can respond to probiotic intervention.
6. Diabetes
Generally systemic inflammation involve microbiota as it
modulates inflammation, interacts with nutrients, influences intestinal
permeability, glucose and lipid metabolism, insulin sensitivity and the
body’s energy balance. The microbiota of diabetic patients is poorly
populated by useful microorganisms (Bifidobacterium, Bacteroides,
Faecalibacterium, Akkermansia, and Roseburia) which have anti-
inflammatory activity, are butyrate-producing and are promoters of
low intestinal permeability and may have inhibitory activity against
carbohydrates-degrading enzymes, reducing postprandial
hyperglycemia. On the contrary, there are many microorganisms
favoring the production of inflammatory molecules and the alteration
of intestinal permeability such as Ruminococcus, Fusobacterium, and
Blautia (112, 113). In any case, considering that diabetes is closely
linked to food choices and habits, it is certainly essential to make
adequate decisions in this regard; for example, an active lifestyle could
improve insulin resistance, while taking foods rich in fibers, largely
represented by prebiotics, is certainly a positive choice for
wise prevention.
Positive effects such as increased insulin sensitivity and
improvement of microbial diversity were found following
administration of L. reuteri DSM 17938 to patients with type 2
diabetes (114).
Toejing et al. (115) administered L. paracasei HII01 (50 × 109 CFU/
day) to 50 T2DM (type 2 diabetes mellitus) patients to evaluate the
effect on glycemia and observed that after 12 weeks fasting blood
glucose (FBG) level significantly decreased. Furthermore, probiotics
reduced the plasma levels of lipopolysaccharide (LPS), inflammatory
markers (TNF-α, IL-6) and C-reactive protein (hsCRP). A reduction
in pathogenic microorganisms together with improvement in
beneficial bacteria were also observed; therefore, the authors
concluded that L. paracasei HII01 could play a potential role as an
adjuvant treatment in type 2 diabetes.
A potential antidiabetic effect was also observed by using another
Lactobacillus strain: Wu et al. (116) investigated the performances of
L. rhamnosus LRa05 on glucose metabolism and gut microbiota in
T2DM mice. The treatment with 109 CFU/day of L. rhamnosus resulted
in a reduction in the fasting blood glucose (FBG) levels (by 53.5%),
lowered insulin resistance, alleviated metabolic lipopolysaccharide-
related inflammation and relieved hepatic oxidative stress. Further
positive effects were found on the gut microbiota composition; in fact,
SCFA producing microorganisms, such as Alloprevotella and
Bacteroides, increased with a reduction of proinflammatory
microorganisms such as Odoribacter and Mucispirillum (116).
Manaer et  al. (117) reported the benefits of Lactobacillus and
yeasts on T2DM mice. Probiotics (Lactobacillus kefiranofaciens,
L. plantarum, Lactobacillus helveticus, L. lactis, Issatchenkia orientalis),
isolated from traditional fermented cheese whey (TFCW), were used
to prepare a mix from camel milk (CPCM) to feed db/db mice. The
authors studied how these strains affect gut microbiota, glucose and
lipid metabolism, liver and renal functions. CPCM reduced fasting
blood glucose (FBG), oral glucose tolerance test and glycosylated
hemoglobin HbAlc, increased C-Protein, modulated lipid metabolism
Frontiers in Nutrition
10.3389/fnut.2023.1209238
and improved liver. Finally, CPCM increased LAB and Bifidobacterium
population in intestinal tract and decreased Escherichia.
Razmpoosh et  al. (118) evaluated the effect of 7 probiotics
(L. acidophilus, L. casei, L. rhamnosus, L. bulgaricus, B. breve,
B. longum, S. thermophilus), and 100 mg of fructo-oligosaccharide
(FOS) with lactose as carriers, on lipid profile and glycemic control in
60 patients. They were equally divided into 2 groups (group 1 took
probiotics and group  2 took a placebo, for 6 weeks). A significant
decrease in the fasting plasma glucose (FPG) and increase of high
density of lipoprotein cholesterol (HDL-C), was observed. No
significant differences in the levels of insulin, triglycerides, total
cholesterol, insulin resistance and anthropometric measurements
(weight, waist circumference and body mass index).
7. Metabolic syndrome
Metabolic syndrome (MetS) is a pathology characterized by an
excess in abdominal fat, arterial hypertension, impaired fasting plasma
glucose (FPG) or insulin resistance, whose diagnoses and treatments
are often similar to those of obesity (119). Supplementary Table S1 lists
6 papers concerning the study of the effect of some probiotics in
subjects with MetS.
Corb Aron et al. (108) and Ottman et al. (93) used A. muciniphila
to evaluate its effect on volunteers with MetS. They observed that the
probiotic degrades mucin by stimulating the production of new
mucous layer (108) and contributes to immune and metabolic
regulation by increasing the intestinal barrier (93). At the same time,
the metabolic activity of A. muciniphila led to the production of SCFA
with beneficial effect to the host and members of the microbiota (93).
Instead L. plantarum (120), L. acidophilus and some
Bifidobacterium species (B. bifidum, B. lactis, and B. longum) (121)
mainly led to a reduction in blood sugar and cholesterol. In particular,
reduction in LDL cholesterol, blood glucose, and homocysteine ​​levels
when postmenopausal women were treated with L. plantarum for
90 days (120).
8. Musculoskeletal system
The role of probiotics in the control of musculoskeletal diseases is
a topic of great interest; osteoporosis (characterized by a decrease in
bone strength, a low mineral density of the bone tissue, with
consequent fragility and aging) (122), osteoarthritis (a
non-inflammatory arthropathy involving cartilage and bone
remodeling) or bone fragility, and microbiota changes are closely
related (123).
It has been demonstrated that the synergistic action of L. casei
with type II collagen (CII) and glucosamine (GS) (potential prebiotic),
administrated to arthritic rats, led to an effective reduction of pain and
cartilage destruction. Moreover, a reduced expression of numerous
proinflammatory cytokines, resulted (124).
Supplementary Table S1 reports some cases concerning the use of
different Lactobacillus strains to relieve bone, joint and muscle
disorders. The ability of probiotics to reduce pain and cartilage
destruction has been highlighted in experiments conducted on
animals (125) together with numerous effects, such as antimicrobial,
antioxidant, anti-inflammatory (126), the ability to determine an
07 frontiersin.org
Campaniello et al.
increase in calcium (127) and recovery of joint strength (128)
in humans.
Steves et al. (125) and Paul et al. (126) demonstrated that L. casei
and L. acidophilus improved intestinal dysbiosis and the symptoms of
rheumatoid arthritis after long-term repeated use thanks to their anti-
inflammatory, antimicrobial and antioxidant properties. These
microorganisms act symbiotically in the intestine to establish their
colonization and consequently increase the integrity of the cell layers
of the gastro-intestinal tract, maintain the nutritional support of the
host and reduce the severity of inflammatory conditions.
9. Immune system disorders
It is known that probiotics can also bring benefits through the
modulation of the immune system. Supplementary Table S1 shows 3
articles focused on the effect of probiotics on the modulation of the
immune system. Among the most significant results, there are the
bactericidal and antitumor effect with production of proinflammatory
and anti-inflammatory cytokines in humans, by E. faecium (95) and
the development of regulatory cells in the gastrointestinal epithelium
in animals, by strains of L. reuteri (99). Finally, Han et al. (129) treated
mice with L. rhamnosus HDB1258 and observed that it enhanced the
immune response by activating innate immunity. In addition,
L. rhamnosus suppressed systemic inflammation by increasing the
expression ratio of anti-inflammatory cytokines and modulated the
microbiota composition.
10. Probiotic species, dose, delivery,
and production
This review shows that there are significant effects of probiotics
on a wide variety of conditions; moreover, a focus at genus/species
level on research papers with a robust design beyond and with proven
effects (ca. 160) suggests the efficacy of lactobacilli (L. plantarum,
L. casei, L. acidophilus, L. reuteri, among others) and bifidobacteria
(B. longum, B. infantis, B. animalis, B. bifidum or B. breve), with
promising evidence for a new generation of probiotics (mainly
A. muciniphila, B. fragilis, and F. prausnitzii; Figure 4). Apart from
species, the identification of the dose required to gain a measurable
output is controversial. Many probiotic supplements contain 1 to
10 billion CFU per dose, up to 50 billion CFU or more; however,
higher CFU counts do not necessarily improve health effects. In fact,
depending on the disorder, it may happen that even a lower dose can
be  effective or even better than a higher dose (130).
Supplementary Table S1 shows the doses, when available, for the
different trials; generally, the concentrations for the most important
commercial preparations of Lactobacillus spp. and Lactobacillus
related genera are from 109 to 1010 CFU, while for Bifidobacterium
spp. at 108–1010 CFU, for Pediococcus acidilactici 109 CFU, for
Streptococcus thermophilus 108 CFU, for yeast strains such as
Saccharomyces boulardii 109 CFU, Bacillus subtilis 109 CFU and
A. muciniphila 108 CFU (131). It is worth mentioning that the dose is
also a function of storage conditions, as some preparations should
be stored at room temperature, while others require refrigeration;
therefore, a thermal abuse could heavily affect probiotic survival. The
International Scientific Association for Probiotics and Prebiotics
Frontiers in Nutrition
10.3389/fnut.2023.1209238
FIGURE 4
Probiotic genera mostly used in clinical trials.
advises manufacturers to list expected probiotic concentration on the
“expiration” or “use by” date on the product label when stored at
proper conditions and suggests consumers to avoid preparations
listing the dose of probiotic at the time of production (132).
Strictly linked to the dose, the second critical point is the duration
of supplementation, but for this aspect there is not a consensus in the
literature; generally, it is believed that probiotics should be assumed
for several weeks (at least from 2 to 4 weeks) to gain achievable
outputs (133). However, the supplementation could be either short-
term or long-term, with short-term interventions suggested only for
acute gastro-intestinal conditions (5–7 days for acute diarrhea in
infants and children, from 1 to 4 weeks for antibiotic-associated
diarrhea, a few weeks for constipation) (133, 134), while other
conditions require long-term supplementation, up to 2–3 months for
IBD, 3–6 months for Chron disease, atopic dermatitis, or psychiatric
diseases (133–136).
Another critical point is the delivery. Probiotics are marketed in
different forms such as capsules, tablets, films, or hydrogels, and for
oral delivery the microencapsulation in hydroxypropyl methylcellulose
phthalate (HPMCP), hydroxypropylmethyl cellulose acetated
succinate, and cellulose acetate phthalate (CAP) is used to minimize
the exposure of probiotics to gastric acids, reducing their viability loss
in the stomach (137). It is a matter of debate if oral delivery mediated
by foods could result in a higher impact of probiotics (138), while
other ways of delivery, less used at least for the studies reported in this
review, are nasal, transdermal, rectal, and vaginal (137).
Also, production could affect viability and thus health effects of
probiotics; fermentation is the most common method of producing
commercial probiotics: in a large fermentation vessel, single-strain
probiotics are inoculated into a liquid broth that is stirred to prevent
bacterial settlement and with pH kept under control. When the
production concerns anaerobic species, gasses such as nitrogen,
hydrogen, and carbon dioxide, are controlled. Microbial growth is
controlled by cell density measurements and light/fluorescence
microscopes are used to check for unwanted contaminations. Once
batch fermentation is complete, a filtered and concentrated cells
suspension is either spray-dried or freeze-dried but previously,
cryoprotectants or lyoprotectants are added to prevent loss of
microbial viability (131).
08 frontiersin.org
Campaniello et al.
To increase the production rate the batch fermentation is
integrated with crossflow membrane ultra/microfiltration; when the
desired cell density is reached, toxic metabolites and/or acids are
removed through a membrane. Fresh medium is continuously
pumped into the fermenter by varying flow rates to ensure a constant
total volume. The cell suspension can then be extracted in batches or
continuously (131).
Another effective method to enhance the production of probiotics
is the immobilization in natural biopolymers such as protein-based
biopolymers, polysaccharides, lipids, and synthetic polymers or
coating for the protection of probiotics against moistures or gasses
(oxygen/carbon dioxide) (131). Cells are immobilized in
polysaccharide hydrogels, then placed in a fermenter, where the
medium is regularly supplemented, and the cells periodically removed
to ensure proper dilution. This strategy is used to improve overall
growth rate and cell viability. The benefits of this approach are the
continuous and controlled delivery of probiotics to the gut, a higher
viability, and lower costs, while the some limits are the restricted
biocompatibility of some immobilization agents, and the complexity
of production processes (131).
11. Conclusions and perspectives
The use of probiotics could be a promising strategy to counteract
side or secondary effects in several pathological conditions; the
evidence and data hereby reported suggest a benefit in CRC both as a
preventive measure to avoid carcinogenesis or during medical
treatments to favor recovery, or in improving cognitive functions, in
ameliorating the symptoms of some intestinal diseases (e.g., IBD), or
to counteract obesity, diabetes and other metabolic syndromes. The
effect is generally mediated through the modulation of gut microbiota,
as well as on the production of significant amounts of SCFA, which
exert in turn several physiological functions, and the final output
could be symptoms amelioration or disease remission, although the
use of different clinical outcomes is a challenge, as it makes difficult a
comparison of different trials and research papers.
At species level, most data are available on Lactobacillaceae and
on Bifidobacterium spp., even if evidence is available for A. muciniphila,
B. fragilis, and F. prausnitzii. However, there are some issues that
should be addressed, related to the duration of the supplementation
(short-term or long-term), dose, as each study suggests a different
dose (ranging from 108 to 1010 CFU). Concerning the way of
supplementation, oral delivery is preferred, but there is still a debate
on the usefulness of a supplementation through food.
References
1. Lederberg J. McCray AT ‘Ome sweet’ omics. A genealogical treasury of words.
Scientist. (2001) 15:8.
2. Aggarwal N, Kitano S, Puah GRY, Kittelmann S, Hwang IY, Chang
MW.  Microbiome and human health: Current understanding, engineering, and
enabling technologies. Chem Rev. (2023) 123:31–72. doi: 10.1021/acs.
chemrev.2c00431
3. Marchesi JR, Adams DH, Fava F, Hermes GDA, Hirscfield GM, Hold G, et al. The
gut microbiota and host health: a new clinical frontier. Gut. (2016) 65:330–9. doi:
10.1136/gutjnl-2015-309990
4. Capurso L. Il Microbiota Intestinale. Recenti Prog Med. (2016) 107:257–66. doi:
10.1701/2296.24680
Frontiers in Nutrition
10.3389/fnut.2023.1209238
Moreover, most papers focus on the medical point of view, while
there is a dark side not addressed, that is the technological story
connected to probiotic productions, the way of supplementation (with
food or as supplements), the shelf life, and the dose at the time of
consumptions, among others. Further efforts are required to address
both medical issues and technological/microbiological challenges for
an effective use of probiotics as concurrent strategies for many
pathological conditions; there are promising evidence and data, but
we are still at a preliminary level, as an effective and efficient use of
probiotics should be based on the clear definition of a “before” (dose,
storage, way of supplementation, duration etc.) and an “after” (outputs
clearly evidenced and defined).
Author contributions
MC, DC, and AB: conceptualization. MS, BS, and AB:
methodology. AR, DC, and AB: investigation and data. AB and DC:
writing–original draft preparation. DC, AB, BS, AR, MS, and MC:
writing–review and editing. MC: supervision. MS and MC: project
administration and funding acquisition. All authors have read and
agreed to the published version of the manuscript.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fnut.2023.1209238/
full#supplementary-material
5. De Siena M, Laterza L, Matteo MV, Mignini I, Schepis T, Rizzatti G, et al. Gut and
Reproductive Tract Microbiota Adaptation during Pregnancy: New Insights for
Pregnancy-Related Complications and Therapy. Microorganisms. (2021) 9:1–15. doi:
10.3390/microorganisms9030473
6. Marangoni F, Poli A. Microbiota intestinale; salute umana e prebiotici. Milano:
Pacini ED (2017).
7. Campaniello D, Corbo MR, Sinigaglia M, Speranza B, Racioppo A, Altieri C, et al.
How diet and physical activity modulate gut microbiota: evidence, and perspectives.
Nutrients. (2022) 14:2456. doi: 10.3390/nu14122456
8. FAO/WHO. Food and Agriculture Organization of the United Nations/World Health
Organization. Joint FAO/WHO expert consultation on evaluation of health and nutritional
09 frontiersin.org
Campaniello et al.
properties of probiotics in food including powder milk with live lactic acid bacteria.
Geneva: World Health Organization (2001).
9. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International
Scientific Association for Probiotics and Prebiotics consensus statement on the scope
and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. (2014)
11:506–14. doi: 10.1038/nrgastro.2014.66
10. Gasbarrini A, Laterza L. La microbiota revolution: nuove conoscenze sul ruolo del
microbiota intestinale e possibili scenari nell’uso dei probiotici In: F Marangoni, P
Restani, L Morelli, A Gasbarrini, L Laterza and D Careddu, editors. Review
sull’integrazione alimentare: evidenza dalla ricerca scientifica e nuove frontiere di sviluppo.
2nd ed. Milano: Edra (2019). 44–8.
11. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. (2014) 44:1–8.
doi: 10.1016/j.medmal.2013.10.002
12. Choden T, Cohen NA. The gut microbiome and the immune system. Expl Med.
(2022) 3:219–33. doi: 10.37349/emed.2022.00087
13. Wu X, Tian J, Wang S. Insight into non-pathogenic Th17 cells in autoimmune
diseases. Front Immunol. (2018) 9:1112. doi: 10.3389/fimmu.2018.01112
14. Ohkubo T, Tsuda M, Suzuki S, El Borai N, Yamamura M. Peripheral blood
neutrophils of germ-free rats modified by in vivo granulocyte-colony-stimulating factor
and exposure to natural environment. Scand J Immunol. (1999) 49:73–7. doi: 10.1046/j.
1365-3083.1999.00456.x
15. Qian LJ, Kang SM, Xie JL, Huang L, Wen Q, Fan YY, et al. Early-life gut microbial
colonization shapes Th1/Th2 balance in asthma model in BALB/c mice. BMC Microbiol.
(2017) 17:135. doi: 10.1186/s12866-017-1044-0
16. Li X, Zhang S, Guo G, Han J, Yu J. Gut microbiome in modulating immune
checkpoint inhibitors. Lancet. (2022) 82:104163. doi: 10.1016/j.ebiom.2022.104163
17. Ye X, Li H, Anjum K, Zhong X, Miao S, Zheng G, et al. Dual role of indoles derived
from intestinal microbiota on human health. Front Immunol. (2022) 13:903526. doi:
10.3389/fimmu.2022.903526
18. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota
and their impact on human metabolism. Gut Microbes. (2016) 7:189–200. doi:
10.1080/19490976.2015.1134082
19. Salvi PS, Cowles RA. Butyrate and the intestinal epithelium: modulation of
proliferation and inflammation in homeostasis and disease. Cells. (2021) 10:1775. doi:
10.3390/cells10071775
20. Godlewska U, Burlanda E, Wypych TP. Bile acids in immunity: bidirectional
mediators between the host and the microbiota. Front Immunol. (2022) 13:949033. doi:
10.3389/fimmu.2022.949033
21. Alexeev EE, Lanis JM, Kao DJ, Campbell EL, Kelly CJ, Battista KD, et al.
Microbiota-derived indole metabolites promote human and murine intestinal
homeostasis through regulation of Interleukin-10 receptor. Am J Pathol. (2018)
188:1183–94. doi: 10.1016/j.ajpath.2018.01.011
22. Ehrlich AM, Pacheco AR, Henrick BM, Taft D, Xu G, Huda MN, et al. Indole-3-
lactic acid associated with Bifidobacterium-dominated microbiota significantly
decreases inflammation in intestinal epithelial cells. BMC Microbiol. (2020) 20:357. doi:
10.1186/s12866-020-02023-y
23. Ménard O, Butel MJ, Gaboriau-Routhiau V, Waligora-Dupriet AJ. Gnotobiotic
mouse immune response induced by Bifidobacterium sp. strains isolated from infants.
Appl Environ Microbiol. (2008) 74:660–6. doi: 10.1128/AEM.01261-07
24. Ponz de Leon M, Rossi G, di Gregorio C, De Gaetani C, Rossi F, Ponti G, et al.
Epidemiology of colorectal cancer: the 21-year of expirience of a specialised registry.
Intern Emerg Med. (2007) 2:269–79. doi: 10.1007/s11739-007-0077-z
25. Dionigi R. Chirurgia - Basi teoriche e Chirurgia generale - Chirurgia specialistica.
Milano: Masson (2019).
26. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence,
mortality, survival, and risk factors. Gastroenterol. (2019) 14:89–103. doi: 10.5114/
pg.2018.81072
27. Grancher A, Michel P, Di Fiore F, Sefrioui D. Aspirin and colorectal cancer. Bull
Cancer. (2018) 105:171–80. doi: 10.1016/j.bulcan.2017.09.013
28. Sánchez-Alcoholado SC, Ordóñez R, Otero A, Plaza-Andrade I, Laborda-Illanes
A, Medina JA, et al. Gut microbiota-mediated inflammation and gut permeability in
patients with obesity and colorectal cancer. Int J Mol. (2020) 21:6782. doi: 10.3390/
ijms21186782
29. Pan SY, DesMeules M. Energy intake, physical activity, energy balance, and cancer:
epidemiologic evidence. Methods Mol Biol. (2009) 472:191–215. doi:
10.1007/978-1-60327-492-0_8
30. Balhareth A, Aldossary MY, McNamara D. Impact of physical activity and diet on
colorectal cancer survivors’ quality of life: a systematic review. World J Surg Oncol. (2019)
17:17–153. doi: 10.1186/s12957-019-1697-2
31. Frezza EE, Wachtel MS, Chiriva-Internati M. Influence of obesity on the risk of
developing colon cancer. Gut. (2006) 55:285–91. doi: 10.1136/gut.2005.073163
32. Minkyeong K, Kyong P. Dietary Fat Intake and Risk of Colorectal Cancer: A
Systematic Review and Meta-Analysis of Prospective Studies. Nutrients. (2018) 10:1963.
doi: 10.3390/nu10121963
Frontiers in Nutrition
10.3389/fnut.2023.1209238
33. Leenders M, Siersema PD, Overvad K, Tjønneland A, Olsen A, Boutron-Ruault
MC, et al. Subtypes of fruit and vegetables, variety in consumption and risk of colon and
rectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int
J Cancer. (2015) 137:2705–14. doi: 10.1002/ijc.29640
34. Zhang SM, Moore SC, Lin J, Cook NR, Manson J, Lee I-M, et al. Folate, vitamin
B6, multivitamin supplements, and colorectal cancer risk in women. Am J Epidemiol.
(2006) 15:108–15. doi: 10.1093/aje/kwj016
35. Park S-Y, Wilkens LR, Setiawan VW, Monroe KR, Haiman CA, Le Marchand L.
Alcohol intake and colorectal cancer risk in the multiethnic cohort study. Am J
Epidemiol. (2019) 1:67–76. doi: 10.1093/aje/kwy208
36. Botteri E, Borroni E, Sloan EK, Bagnardi V, Bosetti C, Peveri G, et al. Smoking and
colorectal cancer risk, overall and by molecular subtypes: A meta-analysis. Am J
Gastroenterol. (2020) 12:1940–9. doi: 10.14309/ajg.0000000000000803
37. Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers. (2013)
5:676–713. doi: 10.3390/cancers5020676
38. Wang T, Cai G, Qiu Y, Fei N, Zhang M, Pang X, et al. Structural segregation of gut
microbiota between colorectal cancer patients and healthy volunteers. ISME J. (2012)
6:320–9. doi: 10.1038/ismej.2011.109
39. Wong SH, Zhao L, Zhang X, Nakatsu G, Han J, Xu W, et al. Gavage of fecal samples
from patients with colorectal cancer promotes intestinal carcinogenesis in germfree and
conventional mice. Gastroenterol. (2017) 153:1621–33. doi: 10.1053/j.gastro.2017.08.022
40. Hou H, Chen D, Zhang K, Zhang W, Liu T, Wang S, et al. Gut microbiota derived
short-fatty acids and colorectal cancer: ready for clinical transition. Cancer Lett. (2022)
526:225–35. doi: 10.1016/j.canlet.2021.11.027
41. Torres-Maravilla E, Boucard AS, Mohseni AH, Taghinezhad SS, Cortes-Perez NG,
Bermudez-Humaran LG. Role of gut microbiota and probiotics in Colorectal Cancer:
Onset and progression. Microorganisms. (2021) 9:1021. doi: 10.3390/
microorganisms9051021
42. Deol PK, Khare P, Bishnoi M, Kondepudi KK, Kaur IP. Coadministration of ginger
extract–Lactobacillus acidophilus (cobiotic) reduces gut inflammation and oxidative
stress via downregulation of COX-2, i-NOS, and c-Myc. Phytother Res. (2018) 32:1950–6.
doi: 10.1002/ptr.6121
43. Ferreira-Halder CV, Faria AVS, Andrade SS. Action and function of
Faecalibacterium prausnitzii in health and disease. Best Prat Res Cl Ga. (2017) 31:643–8.
doi: 10.1016/j.bpg.2017.09.011
44. Saito S, Kakizaki N, Okuno A, Maekawa T, Tsuji NM. Lactococcus lactis subsp.
cremoris C60 restores T cell population in small intestinal lamina propria in aged
Interleukin-18 deficient mice. Nutrients. (2020) 12:3287. doi: 10.3390/nu12113287
45. Iwama T, Fujiva M, Konishi H, Tanaka H, Murakamu Y, Kuonogi T, et al. Bacteria-
derived ferrichrome inhibits tumor progression in sporadic colorectal neoplasms and
colitis-associated cancer. Cancer Cell Int. (2021) 21:21. doi: 10.1186/s12935-020-01723-9
46. Shang F, Jiang X, Wang H, Chen S, Wang X, Liu Y, et al. The inhibitory effects of
probiotics on colon cancer cells: in vitro and in vivo studies. J Gastrointest Oncol. (2020)
11:1224–32. doi: 10.21037/jgo-20-573
47. Dong Y, Zhu J, Zhang M, Ge S, Zhao L. Probiotic Lactobacillus salivarius Ren
prevent dimethylhydrazine-induced colorectal cancer through protein kinase B
inhibition. Appl Microbiol Biotechnol. (2020) 104:7377–89. doi: 10.1007/
s00253-020-10775-w
48. Park IJ, Lee JH, Kye BH, Oh HK, Cho YB, Kim YT, et al. Effects of PrObiotics on
the symptoms and Surgical ouTComes after Anterior REsection of colon cancer
(POSTCARE): A randomized, double-blind, placebo-controlled trial. J Clin Med. (2020)
9:2181. doi: 10.3390/jcm9072181
49. Yoon BJ, Oh HK, Lee J, Cho JR, Kim MJ, Kim DW, et al. Effects of probiotics on
bowel function restoration following ileostomy closure in rectal cancer patients: a
randomized controlled trial. Color Dis. (2021) 23:901–10. doi: 10.1111/codi.15463
50. Sarkar A, Harty S, Lehto SM, Moeller AH, Dinan TG, Dunbar RIM, et al. The
microbiome in psychology and cognitive neuroscience. Trends Cogn Sci. (2018)
22:611–36. doi: 10.1016/j.tics.2018.04.006
51. Kelly JR, Borre Y, Obrien C, Patterson E, El Aidy S, Deane J, et al. Transferring the
blues: depression-associated gut microbiota induces neurobehavioural changes in the
rat. J Psychiatr Res. (2016) 82:109–18. doi: 10.1016/j.jpsychires.2016.07.019
52. Accettulli A, Corbo MR, Sinigaglia M, Speranza B, Campaniello D, Racioppo A,
et al. Psycho-Microbiology, a new frontier for probiotics: An exploratory overview.
Microorganisms. (2022) 10:2141. doi: 10.3390/microorganisms10112141
53. Wieërs G, Belkhir L, Enaud R, Leclercq S, De Foy JMP, Dequenne I, et al. How
probiotics affect the microbiota. Front Cell Infect Microbiol. (2020) 9:454. doi: 10.3389/
fcimb.2019.00454
54. Grimaldi R, Gibson G, Vulevic J, Giallourou N, Castro-Mejía J, Hansen L, et al. A
prebiotic intervention study in children with autism spectrum disorders (ASDs).
Microbiome. (2018) 6:1–13. doi: 10.1186/s40168-018-0523-3
55. Fattorusso A, Di Genova L, Dell’Isola GB, Mencaroni E, Esposito S. Autism spectrum
disorders and the gut microbiota. Nutrients. (2019) 11:521. doi: 10.3390/nu11030521
56. Grossi E, Melli S, Dunca D, Terruzzi V. Unexpected improvement in core autism
spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open
Med Case Rep. (2016) 4:1–5. doi: 10.1177/2050313X16666231
10 frontiersin.org
Campaniello et al.
57. Shaaban SY, El Gendy YG, Mehanna NS, El-Senousy WM, El-Feki HSA, Saad K,
et al. The role of probiotics in children with autism spectrum disorder: A prospective,
open-label study. Nutr Neurosci. (2018) 21:676–81. doi: 10.1080/1028415X.2017.1347746
58. Sanctuary MR, Kain JN, Chen SY, Kalanetra K, Lemay DG, Rose DR, et al. Pilot
study of probiotic/colostrum supplementation on gut function in children with autism
and gastrointestinal symptoms. PLoS One. (2019) 14:e0210064. doi: 10.1371/journal.
pone.0210064
59. Duque ALRF, Demarqui FM, Santoni MM, Zanelli CF, Adorno MAT, Dragan M,
et al. Effect of probiotic, prebiotic, and synbiotic on the gut microbiota of autistic
children using an in vitro gut microbiome model. Food Res Int. (2021) 149:110657. doi:
10.1016/j.foodres.2021.110657
60. Liu YW, Liong MT, Chung YE, Huang HY, Peng WS, Cheng YF, et al. Effects of
Lactobacillus plantarum PS128 on children with autism spectrum disorder in Taiwan: a
randomized, double-blind, placebo-controlled trial. Nutrients. (2019) 11:820. doi:
10.3390/nu11040820
61. Kong XJ, Liu J, Li J, Kwong K, Koh M, Sukijthamapan P, et al. Probiotics and
oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism
spectrum disorders: a pilot randomized controlled trial protocol. Pilot Feasibility Stud.
(2020) 6:20. doi: 10.1186/s40814-020-0557-8
62. Pärtty A, Kalliomäki M, Wacklin P, Salminen S, Isolauri E. A possible link between
early probiotic intervention and the risk of neuropsychiatric disorders later in childhood:
A randomized trial. Pediatr Res. (2015) 77:823–8. doi: 10.1038/pr.2015.51
63. Cheng R, Xu W, Wang J, Tang Z, Zhang M. The outer membrane protein
Amuc_1100 of Akkermansia muciniphila alleviates the depression-like behavior of
depressed mice induced by chronic stress. Biochem Biophys Res Commun. (2021)
566:170–6. doi: 10.1016/j.bbrc.2021.06.018
64. Abildgaard A, Elfving B, Hokland M, Wegener G, Lund S. Probiotic treatment
reduces depressive-like behaviour in rats independently of diet.
Psychoneuroendocrinology. (2017) 79:40–8. doi: 10.1016/j.psyneuen.2017.02.014
65. Reis DJ, Ilardi SS, Punt SEW. The anxiolytic effect of probiotics: a systematic review
and meta-analysis of the clinical and preclinical literature. PLoS One. (2018)
13:e0199041. doi: 10.1371/journal.pone.0199041
66. Wallace CJK, Milev R. The effects of probiotics on depressive symptoms in
humans: a systematic review. Ann General Psychiatry. (2017) 16:14. doi: 10.1186/
s12991-017-0138-2
67. Ghodarz Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, Jafari P, Akbari H,
Taghizadeh M, et al. Clinical and metabolic response to probiotic administration in
patients with major depressive disorder: a randomized, double-blind, placebo-controlled
trial. Nutrition. (2016) 32:315–20. doi: 10.1016/j.nut.2015.09.003
68. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and
anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci
Biobehav Rev. (2019) 102:13–23. doi: 10.1016/j.neubiorev.2019.03.023
69. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic
and prebiotic vs placebo on psychological outcomes in patients with major depressive
disorder: A randomized clinical trial. Clin Nutr. (2019) 38:522–8. doi: 10.1016/j.
clnu.2018.04.010
70. Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, et al. Probiotic
supplementation improves cognitive function and mood with changes in gut microbiota
in community-dwelling older adults: A randomized, double-blind, placebo-controlled,
multicenter trial. J Gerontol A Biol Sci Med Sci. (2021) 76:32–40. doi: 10.1093/gerona/
glaa090
71. Ma T, Jin H, Kwol LY, Sun Z, Liong MT, Zhang H. Probiotic consumption relieved
human stress and anxiety symptoms possibly via modulating the neuroactive potential
of the gut microbiota. Neurobiol Stress. (2021) 14:100294. doi: 10.1016/j.
ynstr.2021.100294
72. Romo-Araiza A, Gutierrez-Salmean G, Galvan EJ, Hernandez-Frausto M, Herrera-
Lopez G, Romo-Parra H, et al. Probiotics and prebiotics as a therapeutic strategy to
improve memory in a model of middle-aged rats. Front Aging Neurosci. (2018) 10:416.
doi: 10.3389/fnagi.2018.00416
73. Kobayashi Y, Kuhara T, Oki M, Xiao JZ. Effects of Bifidobacterium breve a1 on the
cognitive function of older adults with memory complaints: a randomised, double-blind,
placebo-controlled trial. Benef Microbes. (2019) 10:511–20. doi: 10.3920/BM2018.0170
74. Ni Y, Yang X, Zheng L, Wang Z, Wu L, Jiang J, et al. Lactobacillus and
Bifidobacterium Improves physiological function and cognitive ability in aged mice by
the regulation of gut microbiota. Mol Nutr Food Res. (2019) 63:e1900603. doi: 10.1002/
mnfr.201900603
75. Liu J, Sun J, Wang F, Yu X, Ling Z, Li H, et al. Neuroprotective effects of Clostridium
butyricum against vascular dementia in mice via metabolic butyrate. Biomed Res Int.
(2015) 2015:412946. doi: 10.1155/2015/412946
76. Tamtaji OR, Taghizadeh M, Daneshvar Kakhaki R, Kouchaki E, Bahmani F,
Borzabadi S, et al. Clinical and metabolic response to probiotic administration in people
with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Clin
Nutr. (2019) 38:1031–5. doi: 10.1016/j.clnu.2018.05.018
77. Magistrelli L, Amoruso A, Mogna L, Graziano T, Cantello R, Pane M, et al.
Probiotics may have beneficial effects in Parkinson’s Disease: In vitro evidence. Front
Immunol. (2019) 10:969. doi: 10.3389/fimmu.2019.00969
Frontiers in Nutrition
10.3389/fnut.2023.1209238
78. Barichella M, Pacchetti C, Bolliri C, Cassani E, Iorio L, Pusani C, et al. Probiotics
and prebiotic fiber for constipation associated with Parkinson disease: An RCT.
Neurology. (2016) 87:1274–80. doi: 10.1212/WNL.0000000000003127
79. Mendez-Figueroa V, Biscaia JM, Mohedano RB, Blanco-Fernandez A, Bailen M,
Bressa C, et al. Can gut microbiota and lifestyle help us in the handling of anorexia
nervosa patients? Microorganisms. (2019) 7:58. doi: 10.3390/microorganisms7020058
80. Achamrah N, Déchelotte P, Coëffier M. New therapeutic approaches to target gut-
brain axis dysfunction during anorexia nervosa. Clin Nutr Exp. (2019) 28:33–41. doi:
10.1016/j.yclnex.2019.01.006
81. Lew LC, Hor YY, Yusoff NAA, Choi SB, Yusoff MSB, Roslan NS, et al. Probiotic
Lactobacillus plantarum P8 alleviated stress and anxiety while enhancing memory and
cognition in stressed adults: a randomised, double-blind, placebo-controlled study. Clin
Nutr. (2018) 38:2053–64. doi: 10.1016/j.clnu.2018.09.010
82. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria
from the gut microbiota regulate host serotonin biosynthesis. Cells. (2015) 161:264–76.
doi: 10.1016/j.cell.2015.02.047
83. Angelakis E. Weight gain by gut microbiota manipulation in productive animals.
Microb Pathog. (2017) 106:162–70. doi: 10.1016/j.micpath.2016.11.002
84. Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, et al.
Microbiota alteration is associated with the development of stress-induced despair
behavior. Sci Rep. (2017) 7:43859. doi: 10.1038/srep43859
85. Cani PD, de Vos WM. Next-generation beneficial microbes: the case of
Akkermansia muciniphila. Front Microbiol. (2017) 8:1765. doi: 10.3389/fmicb.2017.01765
86. Rezaeiasl Z, Salami M, Sepehri G. The effects of probiotic Lactobacillus and
Bifidobacterium strains on memory and learning behavior, long-term potentiation
(LTP), and some biochemical parameters in β-amyloid-induced rat’s model of
Alzheimer’s Disease. Prev Nutr Food Sci. (2019) 24:265–73. doi: 10.3746/
pnf.2019.24.3.265
87. Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F,
Aghadavod E, et al. Probiotic and selenium co-supplementation, and the effects on
clinical, metabolic and genetic status in Alzheimer’s disease: a randomized, double-
blind, controlled trial. Clin Nutr. (2019) 38:2569–75. doi: 10.1016/j.clnu.2018.11.034
88. Dickerson FB, Stallings C, Origoni A, Katsafanas E, Savage CLG, Schweinfurth
LAB, et al. Effect of probiotic supplementation on schizophrenia symptoms and
association with gastrointestinal functioning: a randomized, placebo-controlled trial.
Prim Care Companion CNS Disord. (2014) 16:13m01579. doi: 10.4088/PCC.13m01579
89. Tankou SK, Regev K, Healy BC, Tjon E, Laghi L, Cox LM, et al. A probiotic
modulates the microbiome and immunity in multiple sclerosis. Ann Neurol. (2018)
83:1147–61. doi: 10.1002/ana.25244
90. Altieri C, Speranza B, Corbo MR, Sinigaglia M, Bevilacqua A. Gut-Microbiota,
and multiple sclerosis: Background, evidence, and perspectives. Nutrients. (2023) 15:942.
doi: 10.3390/nu15040942
91. Eales J, Gibson P, Whorwell P, Kellow J, Yellowlees A, Perry RHJ, et al. Systematic
review and meta-analysis: the effects of fermented milk with Bifidobacterium lactis
CNCM I-2494 and lactic acid bacteria on gastrointestinal discomfort in the general adult
population. Therapeutic Adv Gastroenterol. (2017) 10:74–88. doi:
10.1177/1756283X16670075
92. Lopetuso LR, Quagliarello A, Schiavoni M, Petito V, Russo A, Reddel S, et al.
Towards a disease-associated common trait of gut microbiota dysbiosis: the pivotal role
of Akkermansia muciniphila. Dig Liver Dis. (2020) 52:1002–10. doi: 10.1016/j.
dld.2020.05.020
93. Ottman N, Geerlings SY, Aalvink S, de Vos WM, Belzer C. Action and function of
Akkermansia muciniphila in microbiome ecology, health and disease. Best Pract Res Clin
Gastroenterol. (2017) 31:637–42. doi: 10.1016/j.bpg.2017.10.001
94. Gallo A, Passaro G, Gasbarrini A, Landolfi R, Montalto M. Modulation of
microbiota as treatment for intestinal inflammatory disorders: an uptodate. World J
Gastroenterol. (2016) 22:7186–202. doi: 10.3748/wjg.v22.i32.7186
95. Azad MAK, Sarker M, Li T, Yin J. Probiotic species in the modulation of gut
microbiota: an overview. Biomed Res Int. (2018) 2018:9478630. doi:
10.1155/2018/9478630
96. Dermyshi E, Wang Y, Yan C, Hong W, Qiu G, Gong X, et al. The “Golden Age” of
probiotics: A systematic review and Meta-Analysis of randomized and observational
studies in preterm infants. Neonatology. (2017) 112:9–23. doi: 10.1159/000454668
97. Mezzasalma V, Manfrini E, Ferri E, Sandionigi A, La Ferla B, Schiano I, et al. A
randomized, double-blind, placebo-controlled trial: The efficacy of multispecies
probiotic supplementation in alleviating symptoms of irritable bowel syndrome
associated with constipation. Biomed Res Int. (2016) 2016:4740907. doi:
10.1155/2016/4740907
98. Majeed M, Nagabhushanam K, Natarajan S, Sivakumar A, Ali F, Pande A, et al.
Bacillus coagulans MTCC 5856 supplementation in the management of diarrhea
predominant irritable bowel syndrome: A double blind randomized placebo-controlled
pilot clinical study. Nutr J. (2016) 15:21. doi: 10.1186/s12937-016-0140-6
99. Hemarajata P, Versalovic J. Effects of probiotics on gut microbiota: mechanisms of
intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol. (2013)
6:39–51. doi: 10.1177/1756283X12459294
11 frontiersin.org
Campaniello et al.
100. Lyra A, Hillila M, Huttunen T, Mannikko S, Taalikka M, Tennila J, et al. Irritable
bowel syndrome symptom severity improves equally with probiotic and placebo. World
J Gastroenterol. (2016) 22:10631–42. doi: 10.3748/wjg.v22.i48.10631
101. Sisson G, Ayis S, Sherwood RA, Bjarnason I. Randomised clinical trial: A liquid
multi-strain probiotic vs. placebo in the irritable bowel syndrome–A 12 week double-
blind study. Aliment Pharmacol Ther. (2014) 40:51–62. doi: 10.1111/apt.12787
102. Bervoets L, Van Hoorenbeeck K, Kortleven I, Van Noten C, Hens N, Vael C, et al.
Differences in gut microbiota composition between obese and lean children: a cross-
sectional study. Gut Pathog. (2013) 5:10. doi: 10.1186/1757-4749-5-10
103. Kadooka Y, Sato M, Ogawa A, Miyoshi M, Uenishi H, Ogawa H, et al. Effect of
Lactobacillus gasseri SBT2055 in fermented milk on abdominal adiposity in adults in a
randomised controlled trial. Br J Nutr. (2013) 110:1696–703. doi: 10.1017/
S0007114513001037
104. Omar JM, Chan YM, Jones ML, Prakash S, Jones PJH. Lactobacillus fermentum
and Lactobacillus amylovorus as probiotics alter body adiposity and gut microflora in
healthy persons. J Funct Foods. (2013) 5:116–23. doi: 10.1016/j.jff.2012.09.001
105. Safavi M, Farajian S, Kelishadi R, Mirlohi M, Hashemipour M. The effects of
synbiotic supplementation on some cardio-metabolic risk factors in overweight and
obese children: a randomized triple-masked controlled trial. Int J Food Sci Nutr. (2013)
64:687–93. doi: 10.3109/09637486.2013.775224
106. Asemi Z, Samimi M, Tabasi Z, Talebian P, Azarbad Z, Hydarzadeh Z, et al. Effect
of daily consumption of probiotic yoghurt on lipid profiles in pregnant women: a
randomized controlled clinical trial. J Matern Fetal Neonatal Med. (2012) 25:1552–6.
doi: 10.3109/14767058.2011.640372
107. Jiang J, Wu C, Zhang C, Zhao J, Yu L, Zhang H, et al. Effects of probiotic
supplementation on cardiovascular risk factors in hypercholesterolemia: A systematic
review and meta-analysis of randomized clinical trial. J Funct Foods. (2020) 74:104–77.
doi: 10.1016/j.jff.2020.104177
108. Corb Aron RAC, Abid A, Vesa CM, Nechifor AC, Behl T, Ghitea TC, et al.
Recognizing the benefits of pre−/probiotics in metabolic syndrome and type 2 diabetes
mellitus considering the influence of Akkermansia muciniphila as a key gut bacterium.
Microorganisms. (2021) 9:618. doi: 10.3390/microorganisms9030618
109. Blaak EE, Canfora EE, Theis S, Frost G, Groen AK, Mitheus G, et al. Short chain
fatty acids in human gut and metabolic health. Benef Microbes. (2020) 11:411–55. doi:
10.3920/BM2020.0057
110. Portincasa P, Bonfrate L, Vacca M, De Angelis M, Farella I, Lanza E, et al. Gut
microbiota and short chain fatty acids: implications in glucose homeostasis. Int J Mol
Sci. (2022) 23:1105. doi: 10.3390/ijms23031105
111. Alsharairi NA. The role of short-chain fatty acids in mediating very low-calorie
ketogenic diet-infant gut microbiota relationships and its therapeutic potential in
obesity. Nutrients. (2021) 13:3702. doi: 10.3390/nu13113702
112. Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, et al. Role of gut
microbiota in type 2 diabetes pathophysiology. EBioMedicine. (2020):51102590. doi:
10.1016/j.ebiom.2019.11.051
113. Wang S, Xiao Y, Tian F, Zhao J, Zhang H, Chen W. Rational use of prebiotics for
gut microbiota alterations: specific bacterial phylotypes and related mechanisms. J Funct
Foods. (2020) 66:1–13. doi: 10.1016/j.jff.2020.103838
114. Mobini R, Tremaroli V, Ståhlman M, Karlsson F, Levin M, Ljungberg M, et al.
Metabolic effects of Lactobacillus reuteri DSM 17938 in people with type 2 diabetes: a
randomized controlled trial. Diabetes Obes Metab. (2017) 19:579–89. doi: 10.1111/
dom.12861
115. Toejing P, Khampithum N, Sirilun S, Chaiyasut C, Lailerd N. Influence of
Lactobacillus paracasei HII01 supplementation on glycemia and inflammatory
biomarkers in type 2 diabetes: A randomized clinical trial. Foods. (2021) 10:1455. doi:
10.3390/foods10071455
116. Wu T, Zhang Y, Li W, Zhao Y, Long H, Muhindo EM, et al. Lactobacillus
rhamnosus LRa05 Ameliorate hyperglycemia trough a regulating glucagon-mediated
signaling pathway and gut microbiota in type 2 diabetic mice. J Agric Food Chem. (2021)
69:8797–806. doi: 10.1021/acs.jafc.1c02925
117. Manaer T, Yu L, Nabi XH, Dilidaxi D, Liu L, Sailike J. The beneficial effects of the
composite of probiotics from camel milk on glucose and lipid metabolism, liver and
renal function and gut microbiota in db/db mice. BMC Complement Med Ther. (2021)
21:127. doi: 10.1186/s12906-021-03303-4
118. Razmpoosh E, Javadi A, Ejtahed HS, Mirmiran P, Javadi M, Yousefinejad A. The
effect of probiotic supplementation on glycemic control and lipid profile in patients with
type 2 diabetes: a randomized placebo controlled trial. Diabetes Metab Syndr. (2019)
13:175–82. doi: 10.1016/j.dsx.2018.08.008
119. Zheng J, Cheng G, Li Q, Jiao S, Feng C, Zhao X, et al. Chitin oligosaccharide
modulates gut microbiota and attenuates high-fat-diet-induced metabolic syndrome in
mice. Mar Drugs. (2018) 16:66. doi: 10.3390/md16020066
120. Barreto FM, Colado Simão AN, Morimoto HK, Lozovoy MAB, Dichi MDI, da
Silva H, et al. Beneficial effects of Lactobacillus plantarum on glycemia and homocysteine
levels in postmenopausal women with metabolic syndrome. Nutrition. (2014) 30:939–42.
doi: 10.1016/j.nut.2013.12.004
Frontiers in Nutrition
10.3389/fnut.2023.1209238
121. Kassaian N, Feizi A, Aminorroaya A, Amini M. Probiotic and synbiotic
supplementation could improve metabolic syndrome in prediabetic adults: a randomized
controlled trial. Diabetes Metab Syndr. (2019) 13:2991–6. doi: 10.1016/j.dsx.2018.07.016
122. Porwal K, Pal S, Kulkarni C, Singh P, Sharma S, Singh P. A prebiotic, short-chain
fructo-oligosaccharides promotes peak bone mass and maintains bone mass in
ovariectomized rats by an osteogenic mechanism. Biomed Pharmacother. (2020)
129:1–9. doi: 10.1016/j.biopha.2020.110448
123. Hernandez CJ, Guss JD, Luna M, Goldring SR. Links between the microbiome
and bone. J Bone Miner Res. (2016) 31:1638–46. doi: 10.1002/jbmr.2887
124. So JS, Song MK, Kwon HK, Lee CG, Chae CS, Sahoo A, et al. Lactobacillus casei
enhances type II collagen/glucosamine-mediated suppression of inflammatory
responses in experimental osteoarthritis. Life Sci. (2011) 88:358–66. doi: 10.1016/j.
lfs.2010.12.013
125. Steves CJ, Bird S, Williams FM, Spector TD. The microbiome and musculoskeletal
conditions of aging: a review of evidence for impact and potential therapeutics. J Bone
Miner Res. (2016) 31:261–9. doi: 10.1002/jbmr.2765
126. Paul AK, Paul A, Jahan R, Jannat K, Bondhon TA, Hasan A, et al. Probiotics and
amelioration of rheumatoid arthritis: significant roles of Lactobacillus casei and Lactobacillus
acidophilus. Microorganisms. (2021) 9:1070. doi: 10.3390/microorganisms9051070
127. Gohel MK, Prajapati JB, Mudgal SV, Pandya HV, Singh US, Trivedi SS, et al. Effect
of probiotic dietary intervention on calcium and haematological parameters in
geriatrics. J Clin Diagn Res. (2016) 10:5–9. doi: 10.7860/JCDR/2016/18877.7627
128. Lei M, Hua LM, Wang DW. The effect of probiotic treatment on elderly patients
with distal radius fracture: a prospective double-blind, placebo-controlled randomised
clinical trial. Benef Microbes. (2016) 7:631–7. doi: 10.3920/BM2016.0067
129. Han SK, Shin YJ, Lee DY, Kim KM, Yang SJ, Kim DS, et al. Lactobacillus
rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice
with or without lipopolysaccharide-induced systemic inflammation. BMC Microbiol.
(2021) 21:146. doi: 10.1186/s12866-021-02192-4
130. National Institute of Health. Office of Dietary Supplements Probiotics. Fact sheets
for health professionals. (2022). Available at: https://ods.od.nih.gov/factsheets/Probiotics-
HealthProfessional/ (Accessed June 14, 2023).
131. Hathi Z, Mettu S, Priya A, Athukoralalage S, Lam TN, Choudhury NR, et al.
Methodological advances and challenges in probiotic bacteria production: Ongoing
strategies and future perspectives. Biochem Eng J. (2021) 176:108199. doi: 10.1016/j.
bej.2021.108199
132. International Association for Porbiotics and Prebiotics. Deciphering a probiotic
label. (2022). Available at: http://isappscience.org/wp-content/uploads/2019/04/EU_
Probiotic_labeling_rev1029.pdf (Accessed June 14, 2023).
133. Islam SUI. Clinical uses of probiotics. Medicine. (2016) 95:5. doi: 10.1097/
MD.0000000000002658
134. Miller LE, Lehtoranta L, Lehtinen MJ. Short-term probiotic supplementation
enhances cellular immune function in healthy elderly: systematic review and meta-
analysis of controlled studies. Nutr Res. (2016) 64:1–8. doi: 10.1016/j.nutres.2018.12.011
135. Forth E, Buehner B, Storer A, Sgarbossa C, Milev R, Meyyappan AC. Systematic
review of probiotics as adjuvant treatment for psychiatric disorders. Front Behav
Neurosci. (2023) 17:1111349. doi: 10.3389/fnbeh.2023.1111349
136. Amirami E, Milajerdi A, Mirzaeih JH, Mansournia MA, Hallajzadeh J, et al. The
effects of probiotic supplementation on mental health, biomarkers of inflammation and
oxidative stress in patients with psychiatric disorders: A systematic review and meta-
analysis of randomized controlled trials. Complement Ther Med. (2023) 49:102361. doi:
10.1016/j.ctim.2020.102361
137. Baral KC, Bajracharya R, Lee SH, Han H-K. Advancements in the pharmaceutical
applications of probiotics: dosage forms and formulation technology. Int J Nanomedicine.
(2021) 16:7535–56. doi: 10.2147/IJN.S337427
138. Cunningham M, Vinderola G, Charalampopoulos D, Leeber S, Sanders ME,
Grimaldi R. Applying probiotics and prebiotics in new delivery formats – is the clinical
evidence transferable? Trends Food Sci Technol. (2021) 11:495–506. doi: 10.1016/j.
tifs.2021.04.009
139. Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, et al.
Effects of probiotic supplementation on gastrointestinal, sensory and core symptoms in
autism spectrum disorders: a randomized controlled trial. Front Psych. (2020) 11:550593.
doi: 10.3389/fpsyt.2020.550593
140. Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, et al.
Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. (2015)
138:179–87. doi: 10.1016/j.physbeh.2014.10.033
141. Wang X, Yang J, Zhang H, Yu J, Yao Z. Oral probiotic administration during
pregnancy prevents autism-related behaviors in offspring induced by maternal immune
activation via anti-inflammation in mice. Autism Res. (2019) 12:576–88. doi: 10.1002/
aur.2079
142. El-Ansary A, Bacha AB, Bjørklund G, Al-Orf N, Bhat RS, Moubayed N, et al.
Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile
hamsters induced by orally administered propionic acid and clindamycin. Metab Brain
Dis. (2018) 331155–64. doi: 10.1007/s11011-018-0212-8
12 frontiersin.org